Tetrahydro-pyrido-indole

ABSTRACT

The present invention provides novel tetrahydrobeta-carboline compounds and intermediates having useful central nervous system activity. The invention further provides formulations and methods for using the novel tetrahydrobeta-carboline compounds.

This application is a division of prior application Ser. No. 08/206,830,filed Mar. 11, 1994, now abandoned, which is a continuation in part ofapplication Ser. No. 08/048,392, filed Apr. 14, 1993, now issued U.S.Pat. No. 5,300,645.

FIELD OF THE INVENTION

The present invention relates to the field of organic chemistry. Theinvention provides novel tetrahydro-beta-carboline compounds with a highaffinity for the 5-HT_(1c) receptor.

BACKGROUND OF THE INVENTION

A substantial body of evidence supports the relationship between5-HT_(1c) receptor modulation and a variety of diseases and conditions.

The 5-HT_(1c) receptor subtype was first detected in choroid plexusepithelial cells and is the only 5HT receptor subtype expressed by thesecells. Studies of the 5-HT_(1c) receptor using radioligand binding havebeen complex due to the cross reactivity of the 5-HT_(1c) receptor withthe 5-HT₂ receptor. The discovery of selective, high affinity compoundswhich discriminate between 5-HT_(1c) and 5-HT₂ has been an elusive andimportant target. Hartig et al., The 5-HT_(1c) Receptor Annals New YorkAcademy of Science 149, 159. Compounds with selective affinity for the5-HT_(1c) receptor can provide treatment for 5-HT_(1c)-receptor-mediated conditions without the side effects associated withactivity at the 5-HT₂ receptor. Such compounds can simplifycharacterization of the 5-HT_(1c) receptor and provide useful newtherapeutic agents. In vitro, m-chlorophenylpiperazine (m-CPP) has aslightly higher affinity for the 5-HT_(1c) sites than for other 5-HTreceptors; however, prior to the present invention, there have been noknown 5-HT_(1c) selective ligands.

The activation of the 5-HT_(1c) receptor has been associated withnumerous behavioural and physiological effects. TiPS 11, 181 (May 1990).The 5HT_(1c) receptors in the limbic system can affect mood, behavior,and hallucinogenesis. Hartig et al., The 5-HT_(1c) Receptor Annals NewYork Academy of Science 149, 159. Modulation of the 5HT_(1c) receptorshas been associated with schizophrenia and schizophreniform disorders.Ugedo, L. et. al. Psychopharmacology, 98, 45 (1989); Canton H. et. al.Eur. J. Pharmacol, 191, 93 (1990). Hypothalamic 5-HT_(1c) receptors caninfluence sleep, appetite, thermoregulation, sexual behavior, motoractivity, and neuroendocrine function. Hartig et al., The 5-HT_(1c)Receptor Annals New York Academy of Science 149, 159. Additionally,studies indicate that 5-HT_(1c) receptors mediate hypoactivity, causeddecreased feeding in rats, and have anxiogenic effects. Id. Studies haveshown that drug-induced penile erections are 5-HT_(1c) mediated.Psychopharmacology 101, 57 (1990). Likewise, 5-HT_(1c) modulation cantreat or prevent priapism.

Other studies have used m-CPP to characterize responses associated with5-HT_(1c) receptors. Although responses to 5-HT_(1c) are difficult tocharacterize by this method, the studies evince that 5-HT_(1c) receptorsinfluence the onset of anxiety, obsessive-compulsive disorders, panicdisorders, Gilles de la Tourette syndrome and migraine headaches. TiPS11, 181 (May 1990). The studies indicate that the 5-HT_(1c) receptor canbe involved in Alzheimer's disease as well. Id. The 5-HT_(1c) receptoris involved in the modulation of the balance of cerebrospinal fluid.Further, the 5-HT_(1c) receptor is associated with the sensation ofpain. Zemlan, F. P. et al. Neurochem. Int. 16, 507 (1990).

It would be advantageous to have compounds which would permit modulationof the 5-HT_(1c) receptor. It would be particularly desirable to havecompounds with high 5-HT_(1c) receptor affinity and low 5-HT₂ receptoraffinity. It would be further advantageous to have compounds thatminimize the effects of eating disorders, sexual disorders, and otherdisorders or conditions associated with 5-HT_(1c) modulation.

SUMMARY OF THE INVENTION

This invention provides a group of novel compounds with 5-HT_(1c)receptor activity. The invention also provides compounds with the longedfor selective 5-HT_(1c) receptor antagonist activity. Additionally, thepresent compounds are useful tools to characterize the effects of the5-HT_(1c) receptor and to develop therapeutic agents based on 5-HT_(1c)receptor modulation.

Further, the present invention provides a new method for preparingcompounds with 5-HT_(1c) receptor activity.

This invention relates to a compound of the formula (I) ##STR1##wherein: R₁ is hydrogen or C₁ -C₃ alkyl;

R₂ is hydrogen or C₁ -C₆ alkyl;

R₃ is hydrogen or C₁ -C₃ alkyl;

R₄ is bicyclic or substituted bicyclic;

A is selected from the group consisting of ##STR2## wherein R₆ and R₇are, independently, hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo,halo(C₁ -C₆)alkyl, halo(C₁ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂R_(5'), (C₁ -C₆)_(m) alkylamino, NO₂, --SR₅, or OR₅ ;

m is 1 or 2;

R₅ is independently hydrogen or C₁ -C₄ alkyl;

R_(5') is C₁ -C₄ alkyl;

R₈ is independently selected from the group consisting of an R₆ group,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃)alkyl, C₇ -C₁₆ arylalkyl; or

R₆ and R₇ together with the carbon atoms of group A form a 5- to8-member carbon ring; or

a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides methods of employing, andpharmaceutical formulations containing, a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof.

This invention provides a new process for preparing a compound offormula (VI) ##STR3## wherein R₂ is hydrogen and R₁, R₃, R₄, R₅, R₆, R₇,R₈, and A are as defined supra;

or a pharmaceutically acceptable salt or solvate thereof;

which process comprises contacting a compound of the formula (VII)##STR4## with a lactone of formula (VIII) ##STR5## in the presence of aprotic acid.

DETAILED DESCRIPTION OF THE INVENTION

The term "treating" as used herein includes prophylaxis of the namedphysical and/or mental condition or amelioration or elimination of thedeveloped physical and/or mental condition once it has been established.

The phrase "injury to the central nervous system" includes, but is notlimited to, injury to the spinal cord, neural tube, or dura of thebrain. Injury to the central nervous system also includes priapism,cerebrospinal fluid imbalances, and other 5-HT_(1c) imbalances, andrelated conditions resulting from central nervous system injury.

The terms "C₁ -C_(n) alkyl" wherein n=2-10, as used herein, represent abranched or linear alkyl group having from one to the specified numberof carbon atoms. Typical C₁ -C₆ alkyl groups include methyl, ethyl,n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl,hexyl and the like.

The terms "C₂ -C_(n) alkenyl" wherein n=3-10, as used herein, representsan olefinically unsaturated branched or linear group having from 2 to 10carbon atoms and at least one double bond. The groups can be branched orstraight chain. Examples of such groups include 1-propenyl, 2-propenyl(--CH₂ --CH═CH₂), 1-butenyl (--CH═CHCH₂ CH₃), 1,3-butadienyl(--CH═CHCH═CH₂), hexenyl, pentenyl, and the like.

The terms "halide", "halogen", and "halo" include fluorine, chlorine,bromine, and iodine. The preferred halogen is chlorine.

The terms "halo(C₁ -C₆)alkyl" and "halo(C₂ -C₆)alkenyl" refer to alkylor alkenyl substituents having one or more independently selected haloatoms attached at one or more available carbon atoms. These termsinclude chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl,trifluoroethylenyl, 3-bromopropyl, 3-bromopropenyl, 2-bromopropyl,2-bromopropenyl, 3-chlorobutyl, 3-chlorobutenyl, 3,2-dichlorobutyl,chloroethylenyl, fluoropentenyl, 3-chloro-2-bromohexenyl,3-chloro-2-bromobutyl, trichloromethyl, dichloroethyl,1,4-dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl, 1,1-dichloropropyl,and the like. More preferred halo-(C₁ -C₆)alkyl groups aretrichloromethyl, trichloroethyl, and trifluoromethyl. The most preferredhalo-(C₁ -C₆)alkyl is trifluoromethyl.

The term "C₁ -C₁₀ alkanoyl" represents a group of the formula C(O)(C₁-C₉) alkyl. Typical C₁ -C₁₀ alkanoyl groups include acetyl, propanoyl,butanoyl, and the like.

The term "(C₁ -C₆ alkyl)_(m) amino" wherein m=1-2; refers to either amono- or a dialkylamino group in which the alkyl portion of the groupmay be straight or branched. Examples of such groups are dimethylamino,diethylamino, methylamino, ethylamino, 2-propylamino, 1-propylamino,di(n-propyl)amino, di(iso-propyl)amino, methyl-n-propylamino,t-butylamino, and the like.

The term "C₃ -C_(n) cycloalkyl" wherein n=4-8, represents cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "substituted (C₅ -C_(n)) cycloalkyl" refers to a cycloalkylgroup as described supra wherein the cycloalkyl group may be substitutedwith from one to four substituents independently selected from the groupconsisting of hydrogen, C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, NO₂, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, C₃ -C₈cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁-C₃)alkyl, COR₅, C₁ -C₁₀ alkanoyl, C₇ -C₁₆ arylalkyl, CO₂ R₅, (C₁ -C₆alkyl)_(m) amino, --SR₅, and OR₅.

The term "C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl" represents a linear alkylgroup substituted at a terminal carbon with a C₃ -C₈ cycloalkyl group.Typical cycloalkylalkyl groups include cyclohexylethyl,cyclohexylmethyl, 3-cyclopentylpropyl, and the like.

The term "C₅ -C₈ cycloalkenyl" represents an olefinically unsaturatedring having five to eight carbon atoms, e.g., cyclohexadienyl,cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl,cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like. Thecycloalkenyl group may be substituted with from one to four substituentsselected from the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, (C₁ -C₆alkyl)_(m) amino, COR₅, C₁ -C₁₀ alkanoyl, OR₅, CO₂ R₅, --SR₅, and C₇-C₁₆ arylalkyl.

The term "C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl" represents a linear C₁ -C₃alkyl group substituted at a terminal carbon with a C₅ -C₈ alkenylgroup.

The term "aryl" represents phenyl or naphthyl. The aryl group can beunsubstituted or can have one or two substituents independently selectedfrom the group consisting of C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, C₃ -C₆alkenyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, (C₁ -C₆ alkyl)_(m) amino,phenyl, C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, COR₅, C₁-C₁₀ alkanoyl, OR₅, and C₇ -C₁₆ arylalkyl. The substituents may belocated at any available position on the aryl ring.

The term "C₇ -C₁₆ arylalkyl" represents an aryl(C₁ -C₁₀)alkylsubstituent wherein the alkyl group is linear, such as benzyl,phenethyl, 3-phenylpropyl, or phenyl-t-butyl; or branched.

The term "bicyclic" represents either an unsaturated or saturated stablefused or bridged 7- to 12-membered bicyclic carbon ring. The bicyclicring may be attached at any carbon atom which affords a stablestructure. The bicyclic structure is illustrated by the formula ##STR6##wherein y is independently 1 or 2; w, x, and z are independently 1 to 5;(w+z) is greater than 2; and bonds may be present as necessary to afforda stable structure with the desired degree of saturation. The termincludes, but is not limited to, naphthyl, tetralinyl, decalinyl,compounds of the formula ##STR7## and the like. It is understood thatthe exemplatory structures do not limit the scope of the invention inany way.

The term "substituted bicyclic" refers to a bicyclic ring system withfrom one to four substituents attached at any desired positions on thebicyclic ring system. The bicyclic substituents may be independentlyselected from the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, COR₅, C₁ -C₁₀alkanoyl, C₇ -C₁₆ arylalkyl, CO₂ R₅, (C₁ -C₆ alkyl)_(m) amino, --SR₅,and OR₅ ; wherein m and R₅ are defined supra. It is intended that thesubstituted bicyclic substituent may bond to the CHR₂ group through anyavailable carbon atom in the bicyclic ring system. The term includes,but is not limited to compounds such as, 2-methyltetralinyl,3-hydroxytetralinyl, 4-nitrotetralinyl, 3-dimethylaminonaphthyl,2-methoxynaphthyl, 6-chlorodecalinyl, 8-ethenylnaphthyl, and the like.

The term "naphthyl" refers to a naphthalene ring system substituent, ascommonly used in organic chemistry. The naphthyl substituent may bond tothe CHR₂ group through any available carbon atom in the naphthyl ringsystem. The term "substituted naphthyl" refers to a naphthyl ring systemwith from one to four sustituents attached at any desired positions onthe naphthyl ring system. The naphthyl substituents may be independentlyselected from the "substituted bicyclic" group supra.

The term "phenyl" as used herein refers to an unsubstituted benzene ringsystem. The term "substituted phenyl" refers to a benzene ring systemwith from one to three substituents independently selected from thegroup of bicyclic substituents defined supra.

The term "organic solvent" includes solvents containing carbon, such ashalogenated hydrocarbons, ether, toluene, xylene, benzene, andtetrahydrofuran.

The term "agitate" includes such techniques as stirring, centrifugation,mixing, and other similar methods.

The term "aprotic solvent" refers to polar solvents of moderately highdielectric constant which do not contain an acidic hydrogen. Examples ofcommon aprotic solvents are dimethyl sulfoxide (DMSO),dimethylformamide, sulfolane, tetrahydrofuran, ether, methyl-t-butylether, or 1,2-dimethoxyethane.

The term "protic solvent" refers to a solvent containing hydrogen thatis attached to oxygen, and hence is appreciably acidic. Common proticsolvents include such solvents as water, methanol, ethanol, 2-propanol,and 1-butanol.

The term "inert atmosphere" refers to reaction conditions in which themixture is covered with a layer of inert gas such as nitrogen or argon.

The term "protic acid" refers to an acid having an acidic hydrogen.Preferred protic acids include hydrochloric acid, formic acid,perchloric acid, sulfuric acid, and phosphoric acid in an aqueousmedium. The most preferred protic acids are hydrochloric acid, sulfuricacid, and formic acid.

The term "selective binding of a 5-HT_(1c) receptor" refers to a methodof binding the 5-HT_(1c) receptor to a greater extent than it binds the5-HT₂ receptor.

The term "substantially pure" is intended to mean at least about 90 molepercent, more preferably at least about 95 mole percent, and mostpreferably at least about 98 mole percent of the desired enantiomer orstereoisomer is present compared to other possible configurations.

The term "ligand" refers to compounds that are bound by the 5-HT_(1c)receptor. Compounds useful as 5-HT_(1c) selective ligands may be used toselectively occupy the 5-HT_(1c) receptor site or may act as a selectiveagonist at the 5-HT_(1c) receptor site.

The abbreviations used herein have their accepted meaning, unless statedotherwise. For example, "Me" and "Et" refer to methyl, ethylrespectively, and "t-Bu" refers to tertiary-butyl. The abbreviation "RT"refers to room temperature or ambient conditions unless indicatedotherwise.

The abbreviation "TMEDA" refers to tetramethylethylenediamine. "THF"refers to tetrahydrofuran. "MOMCI" refers to chloromethylmethyl ether."Ph" refers to a phenyl group

The terms "MeO" and "EtO" refer to methoxy and ethoxy substituents whichare bound to the parent molecule through the oxygen.

The formula (I) compounds can form acid addition salts with a widevariety of inorganic and organic acids. Typical acids which can be usedinclude sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric,hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric,cinnamic, benzoic, ascorbic, mandelic, p-toluenesulfonic,benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and thelike. The pharmaceutically acceptable acid addition salts of the formula(I) are especially preferred.

The compounds of the present invention are useful for modulating orblocking the 5-HT_(1c) receptor. Certain of the present compounds arepreferred for that use. Preferred compounds are those having thefollowing characteristics:

A) R₁ is hydrogen;

B) R₂ is hydrogen or methyl;

C) R₃ is hydrogen or methyl;

D) R₄ is naphthyl or substituted naphthyl wherein the naphthylsubstituents are selected from the group consisting of (C₁ -C₆alkyl)_(m) amino and OR₅ ;

E) A is a group of formula III;

F) A is a group of formula IV wherein R₆ and R₇ are independentlyselected from the group consisting of hydrogen, C₁ -C₅ alkyl, and halo.R₈ is independently selected from the group consisting of hydrogen, C₁-C₅ alkyl, halo, C₅ -C₈ cycloalkyl, phenyl and substituted-phenyl;

G) R₂ is hydrogen;

H) R₃ is hydrogen;

I) R₄ is naphthyl, or substituted naphthyl wherein the substituents areselected from dialkylamino and OR₅ ;

J) A is a group of formula IV wherein R₆ is hydrogen, R₇ is hydrogen ormethyl, and R₈ is C₁ -C₄ alkyl, Br, or F.

The more preferred classes of compounds have the following features:

A-C, E or F and I.

The most preferred class has the following features:

A and G-J.

The preferred classes of compounds for use as selective 5-HT_(1c)ligands have the following features:

A-D and E or J.

The most preferred class of compounds for use as selective 5-HT_(1c)ligands has the following features:

A and G-J.

The Formula (I) compounds have useful central nervous system activity.Table I illustrates several of the Formula (I) compounds. The terms inthe column headings of Table I refer to Formula (I). As used in thetable, the headings "S₁ ", "S₂ ", and "S₃ " refer to the substituents onthe R₄ group. ##STR8##

The abbreviations for the R₄ group refer to the following: ##STR9##

                                      TABLE I                                     __________________________________________________________________________    A R.sub.1                                                                          R.sub.2                                                                           R.sub.3                                                                          R.sub.4                                                                          S.sub.1                                                                            S.sub.2                                                                           S.sub.3                                                                           R.sub.6                                                                            R.sub.7                                                                           R.sub.8                                  __________________________________________________________________________    II                                                                              H  H   H  R.sub.4A                                                                         OH   t-Bu                                                                              H   NHPr H   H                                        III                                                                             Me Me  Me R.sub.4B                                                                         OMe  OMe H   Me   Me  H                                        IV                                                                              Et Et  Et R.sub.4C                                                                         NMe.sub.2                                                                          H   H   C.sub.2 H.sub.3                                                                    H   Cl                                       IV                                                                              H  C.sub.6 H.sub.13                                                                  Pr R.sub.4D                                                                         NBu.sub.2                                                                          H   H   H    C.sub.3 H.sub.5                                                                   Br                                       III                                                                             Me C.sub.5 H.sub.11                                                                  H  R.sub.4E                                                                         NPr.sub.2                                                                          H   H   H    H   H                                        IV                                                                              Et C.sub.4 H.sub.9                                                                   Me R.sub.4F                                                                         NEt.sub.2                                                                          H   H   H    H   H                                        III                                                                             H  C.sub.3 H.sub.7                                                                   Et R.sub.4G                                                                         NHMe H   H   H    H   C.sub.4 H.sub.7                          II                                                                              Me C.sub.3 H.sub.5                                                                   Pr R.sub.4H                                                                         NHBu H   NHMe                                                                              H    H   H                                        III                                                                             Et Pr  H  R.sub.4I                                                                         NHPr H   H   H    H   H                                        IV                                                                              Pr Bu  Me R.sub.4J                                                                         NHEt H   NMe.sub.2                                                                         Et   H   Me                                       II                                                                              H  H   Et R.sub.4K                                                                         CH.sub.2 Cl                                                                        H   H   C.sub.2 H.sub.3                                                                    Cl  F                                        III                                                                             Pr Me  H  R.sub.4L                                                                         H    Br  H   OH   C.sub.3 H.sub.5                                                                   H                                        IV                                                                              Et Et  Me R.sub.4M                                                                         OH   OMe F   H    H   Ph                                       II                                                                              Pr H   Et R.sub.4N                                                                         NO.sub.2                                                                           H   H   OH   OMe H                                        III                                                                             Me Me  H  R.sub.4O                                                                         H    Cl  Me  Pr   Me  F                                        IV                                                                              H  H   H  R.sub.4P                                                                         OMe  H   H   H    OMe OMe                                      III                                                                             Me Me  Me R.sub.4Q                                                                         H    OMe H   Me   H   H                                        II                                                                              Et Et  Et R.sub.4R                                                                         H    H   OMe OBu  F   H                                        IV                                                                              Pr Pr  Pr R.sub.4S                                                                         H    OMe H   OEt  Cl  H                                        III                                                                             H  Bu  H  R.sub.4T                                                                         H    H   H   OH   Me  H                                        II                                                                              Me H   Me R.sub.4U                                                                         H    OH  H   Me   H   Br                                       IV                                                                              Et Me  Et R.sub.4V                                                                         F    Cl  H   H    H   H                                        III                                                                             Pr H   Pr R.sub.4X                                                                         Cl   OMe OMe Cl   NMe.sub.2                                                                         NO.sub.2                                 II                                                                              H  Me  Pr R.sub.4Y                                                                         Br   Br  OMe Me   Et  H                                        IV                                                                              Me Et  Et R.sub.4Z                                                                         CO.sub.2 C.sub.2 H.sub.5                                                           H   H   COC.sub.2 H.sub.5                                                                  H   Me                                       III                                                                             Et Pr  Me R.sub.4D                                                                         OMe  OMe OMe H    H   H                                        IV                                                                              Pr Bu  H  R.sub.4E                                                                         H    H   H   Me   F   F                                        III                                                                             H  C.sub.5 H.sub.11                                                                  Me R.sub.4F                                                                         OMe  OMe OMe NMe.sub.2                                                                          H   Cl                                       IV                                                                              Me C.sub.6 H.sub.13                                                                  Me R.sub.4G                                                                         F    OEt H   C.sub.2 H.sub.4 Cl                                                                 H   F                                        III                                                                             Et H   H  R.sub.4H                                                                         Cl   OH  Br  OEt  OMe OH                                       IV                                                                              H  H   Pr R.sub.4I                                                                         NO.sub.2                                                                           OMe OMe H    Me  H                                        II                                                                              Et Me  H  R.sub.4J                                                                         Cl   OH  Br  H    Me  OMe                                      III                                                                             Me Et  H  R.sub.4K                                                                         Cl   OMe OH  Et   H   H                                        IV                                                                              Et H   Et R.sub.4L                                                                         H    H   SH  C.sub.2 H.sub.3                                                                    Cl  H                                        III                                                                             Pr Me  H  R.sub.4M                                                                         H    F   NHBu                                                                              H    H   C.sub.4 H.sub.7                          IV                                                                              H  H   Pr R.sub.4N                                                                         COMe H   H   OH   OMe H                                        II                                                                              Me Bu  H  R.sub.4O                                                                         OMe  NMe.sub.2                                                                         H   H    H   Ph                                       IV                                                                              Et H   Me R.sub.4P                                                                         OEt  NMe.sub.2                                                                         OMe NO.sub.2                                                                           t-Bu                                                                              H                                        III                                                                             H  Me  H  R.sub.4Q                                                                         H    H   NO.sub.2                                                                          Pr   Me  H                                        III                                                                             Me Et  Me R.sub.4R                                                                         H    F   H   F    Me  F                                        II                                                                              Et Pr  H  R.sub.4S                                                                         CO.sub.2 H                                                                         H   H   H    H   C.sub.3 H.sub.5                          IV                                                                              H  Bu  H  R.sub.4T                                                                         Br   Cl  H   Et   H   Me                                       III                                                                             Me C.sub.4 H.sub.9                                                                   H  R.sub.4U                                                                         H    OMe Cl  Cl   Me  Cl                                       II                                                                              Et H   Pr R.sub.4V                                                                         H    F   OH  H    H   H                                        IV                                                                              H  Me  Me R.sub.4W                                                                         Cl   OMe H   H    H   H                                        __________________________________________________________________________

The present invention contemplates racemic mixtures as well as thesubstantially pure stereoisomers of the compounds of Formula I. The term"enantiomer" is used herein as commonly used in organic chemistry todenote a compound which rotates the plane of polarization. Thus, the"-enantiomer" rotates the plane of polarized light to the left, andcontemplates the levorotary compound of Formula I. The + and-enantiomers can be isolated using classical resolution techniques. Oneparticularly useful reference which describes such methods is JACQUESet. al. ENANTIOMERS, RACEMATES, AND RESOLUTIONS (John Wiley and Sons1981). Appropriate resolution methods include direct crystallization,entrainment, and crystallization by optically active solvents. Chrisey,L. A. Heterocycles, 267, 30 (1990). A preferred resolution method iscrystallization with an optically active acid or by chiral synthesis asdescribed in Example 46 using the method of A. I. Meyers. Loewe, M. F.et al., Tetrahedron Letters, 3291, 26 (1985), Meyers, A. I. et al., J.Am. Chem. Soc. 4778, 110 (1988). Preferred optically active acidsinclude camphorsulfonic and derivatives of tartaric acid.

For example the invention includes, but is not limited to compounds suchas(-)-(S)-6-methyl-1-[(4-dimethylamino-naphthalenyl)-methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,(-)-(S)-6-methyl-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,(-)-(S)-6-(1,1-dimethylethyl)-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,and(-)-(S)-6-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4b]indole.The invention also includes, but is not limited to,(+)-(S)-6-methyl-1-[(4-dimethylaminonaphthalenyl)-methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,(+)-(S)-6-methyl-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,(+)-(S)-6-(1,1-dimethylethyl)-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,and(+)-(S)-6-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4b]indole.

The compounds of the present invention are known to form hydrates andsolvates with appropriate solvents. Preferred solvents for thepreparation of solvate forms include water, alcohols, tetrahydrofuran,DMF, and DMSO. Preferred alcohols are methanol and ethanol. Otherappropriate solvents may be selected based on the size of the solventmolecule. Small solvent molecules are preferred to facilitate thecorresponding solvate formation. The solvate or hydrate is typicallyformed in the course of recrystallization or in the course of saltformation. One useful reference concerning solvates is Sykes, Peter, AGuidebook to Mechanism in Organic Chemistry, 56+, 6th Ed (1986, JohnWiley & Sons, New York). As used herein, the term "solvate" includeshydrate forms, such as monohydrates and dihydrates.

The compounds of the present invention can be prepared using chemicalprocesses that are understood in the art; however, the most preferredmethod for preparing the formula (I) compounds of this inventionutilizes a novel process which is illustrated in Scheme V. The processof Scheme V is a Pictet-Spengler type reaction.

Traditionally, the Pictet-Spengler reaction consists of the condensationof a β-arylethylamine with a carbonyl compound to yield atetrahydroisoquinoline. Pictet et. al. 44 Ber. 2030 (1911). ThePictet-Spengler reaction has been extended to the condensation ofsubstituted amines and tryptamines with various aldehydes. Decker et.al. 395 Ann. 342 (1913). Unfortunately, the known Pictet-Spenglerreaction often requires drastic reaction conditions, results inundesired by-products, and the effectiveness of the reaction is closelyrelated to the carbonyl compound used in the reaction. Shono et. al. 48J. Org. Chem. 1621-1628 (1983). The traditional Pictet-Spengler carbonylcompounds are acetaldehyde derivatives which may be tedious to prepareand isolate. Often the overall yield using the traditionalPictet-Spengler reaction is undesirably low. The new process of thisinvention utilizes naphthaldehydes which are simple to prepare.

This Pictet-Spengler type reaction is generally applicable, providesdesirable yields, and produces stable intermediates. Further, theproduct of the reaction typically may be directly isolated as thedesired salt.

Surprisingly, Applicants have discovered that compounds of formula I,wherein R₂ is hydrogen, may be prepared by contacting a lactone compoundof formula (i) with an amine of formula (h) in the presence of a proticacid. This Pictet-Spengler type reaction is generally applicable,provides desirable yields, and produces stable intermediates. Further,the product of the reaction typically may be directly isolated as thedesired salt.

The compounds of formula (a) which may be used as starting materials forthe compounds of the instant invention can be purchased fromart-recognized vendors or may be prepared using well-known chemicaltechniques. Furniss, Brian S. et al., Vogel's Textbook of PracticalOrganic Chemistry, 989-993, 5th Ed. (1989, John Wiley & Sons, New York).The compounds of formula (b) which are useful as starting materials forthe compounds of this invention may be prepared as represented by SchemeI. The R₄ group is as defined herein above.

The process for preparing the compounds of this invention will bediscussed in greater detail in the following paragraphs. ##STR10##

Compound (a) in Scheme I may be substituted or unsubstituted dependingon the desired product. Most formula (a) compounds necessary for thepreparation of the azalactone (b) starting materials are commerciallyavailable. Additional substituted formula (a) compounds may preparedusing common chemical methods. Furniss, Brian S. et al., Vogel'sTextbook of Practical Organic Chemistry, 989-993, 5th Ed. (1989, JohnWiley & Sons, New York).

Generally, the Scheme I reaction is begun by preparing a solution ofcompound (a), acetylglycine and sodium acetate in acetic anhydride. Thereaction is commonly heated from about 90° C. to about 110° C. for aperiod of about 2-15 hours. The reaction mixture is cooled to aboutambient temperature and stirred for a period of about 0-10 hours underinert conditions. The reaction time will vary depending on the degree ofsubstitution on the bicyclic ring and the completion of reactiondesired.

When the reaction is complete, the mixture is poured onto ice withstirring. The azalactone (b) may be isolated by standard isolationtechniques such as filtration and may be dried under reduced pressure.

Compound (d) in Scheme II is used as a starting material for compoundsof formula (I). These compounds are commercially available or may beprepared using a modification of the well-known Fischer indole synthesisusing tryptamines. The modified Fischer synthesis is represented byScheme II. "A" is as hereinabove defined. ##STR11##

The chlorobutanal compound used in Scheme II may be prepared through thehydrogenation of chlorobutyryl chloride. Other halobutanal compounds maybe suitable for the Scheme II hydrogenation. The hydrogenation may befacilitated by the use of a catalyst such as Pd/C. The startingcompounds (c) in Scheme II may be purchased or prepared using knownmethods. March, Jerry, Advanced Organic Chemistry, 1163, 3rd (1985, JohnWiley & Sons, New York).

The modified Fischer synthesis is commonly begun by adding a suitablesaturated base like sodium carbonate to a stirred suspension of thehydrazine salt in an organic solvent like chloroform. The hydrazinehydrochloride salt is one especially preferred hydrazine salt. Thedesired hydrazine free base is extracted with the organic phase. The oilis placed in an alcohol and water solution and treated with anappropriate base like sodium acetate. The halobutanal is added and thetube purged with an inert gas like nitrogen. The resulting mixture isplaced in an oil bath which has been heated to about 90° C.-110° C. Themixture should be heated for about 17 to 19 hours. The mixture isallowed to cool to ambient temperature and is concentrated under reducedpressure. The residue is partitioned between a suitable organic andbasic aqueous phase, such as chloroform/methanol and aqueous sodiumcarbonate. The organic phase may be concentrated and the resultingcompound (d) purified by standard methods such as flash chromatography.If chromatography is used, fractions containing product may be combinedand concentrated. The oil is dissolved in an appropriate solvent, suchas diethyl ether containing about 1% alcohol. A preferred alcohol ismethanol. The mixture may be treated with dry acid gas, such as dry HClgas to produce the corresponding acid addition salt of the desiredcompound (d).

One method for preparing Formula (I) compounds uses the Pictet-Spenglerreaction as represented by Scheme III. The substituents are as definedhereinabove. ##STR12##

Generally, the Scheme III reaction is carried out by refluxing compound(e) with the selected aldehyde in a suitable solvent such as ethanol ormethanol for a period of about 35 to 50 hours. The precipitated reactionproduct (f) is collected by common isolation methods, such as filtrationand may be purified by recrystallization. If a compound with an R₁substituent is desired, the reaction may be followed by a reductivealkylation. The reductive alkylation is represented by Scheme IV.##STR13##

A protic acid and aldehyde solution is commonly added to an aqueoussolution of compound (f). The most preferred protic acid is formic acid.The most preferred aldehyde is formaldehyde. The artisan can readilychoose other appropriate reagents for the reductive alkylation. Theresulting solution is refluxed for a period of about 60 to 80 hours.After reflux the solution should be made basic using an appropriate basesuch as potassium carbonate. The desired product can then be extractedwith an appropriate organic phase, such as chloroform. The product canbe dried, concentrated, and purified by known methods such as flashchromatography.

A preferred method for preparing Formula (I) compounds, wherein R₂ ishydrogen, utilizes a new modified Pictet-Spengler reaction, describedsupra, as represented by Scheme V. The substituents are as definedhereinabove. ##STR14##

Compound (h) and compound (i) are contacted in a suitable protic aqueousacid solution under inert conditions. Most preferably, compound (h) andcompound (i) are refluxed under inert conditions for a period of about20 to about 30 hours. Preferred protic acids include formic acid andhydrochloric acid. The most preferred acid solution is 1N HCl. If directisolation is not effective, then the reaction mixture may be neutralizedwith an appropriate base, such as potassium carbonate, followed byextraction with an organic phase, such as chloroform. The product can beisolated through solvent removal followed by chromatographic isolation,such as silica gel chromatography, or other common isolation techniques.Typically the product is isolated as the acid addition salt. Appropriatesalt forms are discussed supra.

As noted above, the compounds of the present invention can exist asresolved enantiomers. The single (-) enantiomer may be prepared by themethod of A. I. Meyers as represented by Scheme VI infra. The (+)enantiomer may be prepared using known resolution techniques describedsupra. All substituents are as defined hereinabove. ##STR15##

In Scheme VI, CSA represents camphorsulfonic acid. Butylformadine (1) isprepared from the amino acid valine using known methods. Other formadinecompounds will also work. In step 1, the compound (k) and butylformadine(l) solution is refluxed for a period of about 70 to 80 hours. Theproduct of the reflux reaction can be purified by standard isolationmethods, such as flash chromatography. The isolated oil can be usedwithout further purification.

Compound (m) prepared in step 1, can be added to a suspension ofpotassium hydride (KH) in tetrahydrofuran (THF).Tetramethylethylenediamine (TMEDA), and then chloromethylmethyl ether(MOMCl) are added to the solution, as represented by step 2. The mixtureis stirred for a period of about 1 hour. The mixture can be treated withwater and partitioned between an appropriate organic, such as diethylether, and water. The product should be extracted with the organicphase, dried over potassium carbonate, and concentrated. The resultingoil may be used in subsequent steps without further purification.

In step 3, n-BuLi is slowly added dropwise to a stirred, cooled (about-76° C. to -80° C.) solution of the formadine in dry THF. The solutionis stirred for a period of about 1 hour followed by addition of thechloro compound in dry THF. The solution is stirred for an additionalperiod of about 4-5 hours at the reduced temperature. The mixture isallowed to cool to room temperature for a period of about 4 to 14 hours.Wet THF is added and the solution concentrated. The residue is dissolvedin an appropriate organic solvent such as chloroform and washed withwater. The organic phase is dried over a suitable drying agent, such assodium carbonate, and concentrated to facilitate purification of thedesired product. The product may be isolated by flash chromatography andconcentrated. The resulting oil may be used in subsequent steps withoutfurther purification.

The deprotection reaction represented in step 4 is begun at reducedtemperature (about 0° C.). Water, acetic acid, and hydrazine hydrate areadded to compound (o). The reaction temperature is decreased to about-10° C. to -20° C. for a period of about 60-120 hours. The mixture isallowed to warm to ambient temperature and is concentrated. The productis dissolved in an appropriate organic phase, such as chloroform, andwashed with water. The organic phase is dried over a suitable dryingagent, such as sodium carbonate, and concentrated to a viscous oil. Theoil is dissolved in an appropriate solvent, such as diethyl ether andtreated with a suitable organic or inorganic acid to afford the desiredacid addition salt. The salt can be isolated and purified by commonchemical methods.

If the desired product has an alkyl group at the R₃ position, thereaction represented by Scheme VII may be employed. ##STR16##

In Scheme VII, an appropriate saturated base solution, such as sodiumcarbonate, is added to compound (q). The desired compound (q) salt maybe prepared by the method of Scheme II, above. The mixture is stirred atabout ambient temperature for a period of about 1 hour. The layers areseparated, and the aqueous layer is extracted with an appropriateorganic solvent, such as chloroform. The organic layers are dried overan appropriate drying agent, such as sodium sulfate, and concentrated.The residue is dissolved in a suitable solvent such as toluene andtreated with phthalic ##STR17## anhydride. The solution is refluxed fora period of about 12 to 20 hours with azeotropic drying. The solution iscooled, concentrated, and recrystallized to give compound (r).

Compound (r) is mixed in THF. A cooled (about 0° C.) suspension of anappropriate base, such as potassium hydride in dry THF, is slowly addedto the compound (r) solution. After the addition of the the base, themixture is stirred for a period of about 1 hour.Tetramethylethylenediamine (TMEDA) is added, followed by a haloalkylsuch as methyl iodide (MeI). After about 1 hour, the reaction isquenched by the addition of water, followed by extraction with anappropriate organic phase, such as diethyl ether. The organic phases aredried over an appropriate drying agent, such as magnesium sulfate andconcentrated.

A solution of the concentrated compound (s) (above) is contacted with anappropriate solvent, such as methanol, and treated with hydrazine. Themixture is refluxed for a period of about 2 hours. The mixture is cooledto ambient temperature and treated with concentrated acid, such as HCl.The mixture is then treated with an alcohol and refluxed for a period ofabout 12 to 20 hours. Preferred alcohols include methanol, ethanol, andbutanol. After cooling to ambient temperature, the mixture ispartitioned between a suitable organic and an aqueous phase. Onesuitable combination is chloroform and concentrated sodium carbonatesolution. The aqueous layer may be further extracted, the organic phasescombined, dried, and concentrated. The product may be purified by flashchromatography, concentrated, and converted to a desired salt. Theresulting compound (t) may be used in Scheme III or Scheme V to producethe desired Formula (I) compounds.

The following Examples further illustrate certain of the compounds ofthe present invention, and methods for their preparation. The examplesare illustrative only, and are not intended to limit the scope of theinvention.

The column chromatography procedures used standard flash chromotagraphytechniques. One well-known reference describing appropriate flashchromotagraphy techniques is Still, W. C. Kahn, and Mitra, J. Org. Chem.1978, 43, 2932. Fractions containing product were generally evaporatedunder reduced vacuum to provide the product.

Optical rotations were obtained using methanol, pyridine, or othersuitable solvent.

The hydrochloride salt of the particular compound was prepared byplacing the free base into diethyl ether. While stirring this ethersolution, a solution of HCl in diethyl ether was added dropwise untilthe solution became acidic. Alternatively, the ether solution wastreated with dry HCl gas.

The maleate salt of the particular compound was prepared by placing thefree base in ethyl acetate and treating with maleic acid. Theprecipitate formed was filtered and dried to provide the correspondingmaleate salt of the free base.

EXAMPLE 1 Preparation of (±)6-methyl-1-(1-(4-methoxynaphthalenyl)methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR18##

A solution of 4-methoxy-1-naphthaldehyde (20.0 g, 0.107 mol),N-acetylglycine (12.58 g, 0.107 mol) and sodium acetate (8.81 g, 0.107mol) in acetic anhydride (100 mL) was heated to 100° C. for 2 hours. Thereaction mixture was cooled to ambient temperature and stirred for 10hours under nitrogen atmosphere. The mixture was poured onto ice (250mL) with stirring. The product was isolated by filtration, washed withwater (3×50 mL) and diethyl ether (3×50 mL) and dried under reducedpressure (3.16 g). ##STR19##

A suspension of azalactone prepared above (2.00 g, 7.5 mmol) and5-methyltryptamine hydrochloride (1.18 g, 5.62 mmol) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The brown solid was triturated with isopropylalcohol (3×50 mL) and washed with diethyl ether (3×50 mL).Recrystallization from ethanol afforded 1.42 g of desired product as apale solid. (mp 271.7° C.)

    ______________________________________                                        Analysis:      Calculated                                                                              Found                                                ______________________________________                                        C              73.36     73.60                                                H              6.41      6.51                                                 N              7.13      7.20                                                 ______________________________________                                    

EXAMPLE 2 Preparation of (±)6-methyl-1-(1-(2-methoxynaphthalenyl)methyl)1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR20##

To a stirred, cooled (-78° C.) solution ofmethoxymethyl-triphenylphosphonium chloride (11.05 g, 32.2 mmol) in 150mL of anhydrous THF was added n-butyllithium (20.14 mL of 1.6M solutionin hexanes, 32.2 mmol) dropwise via syringe. After complete addition,the solution was stirred at this temperature for 15 min. A solution of2-methoxy-1-naphthaldehyde (5.0 g, 26.9 mmol) in THF (75 mL) was addedto the solution dropwise by addition funnel. After complete addition,the solution was allowed to warm to ambient temperature and stir for 14hours. A saturated solution of ammonium chloride (100 mL) was added andthe mixture was partitioned between diethyl ether and water. The organicphase was dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The crude residue was purified by plugfiltration (silica gel, eluent 40% ethyl acetate/hexanes) and afforded5.0 g of product as a mixture of enol ethers, which was used withoutfurther purification. ##STR21##

A solution of enol ethers prepared above (5.0 g, 23.3 mmol) in diethylether (50 mL) was treated with water (1.0 mL) and perchloric acid (1.5mL of 60% solution). The solution was stirred at ambient temperature for72 hours. The solution was diluted with chloroform (100 mL) andneutralized with saturated sodium bicarbonate solution. The mixture wasextracted with chloroform (3×100 mL) and the combined organic phaseswere dried over sodium sulfate and concentrated. The residue waspurified by flash chromatography on silica gel (5% diethyl ether/hexanesas eluent) to afford (2-methoxy-1-naphthyl)-acetaldehyde (1.79 g) as acolorless oil. ##STR22##

To a stirred solution of 5-methyltryptamine hydrochloride (947 mg, 4.49mmol) in 20 mL of ethyl alcohol was added(2-methoxy-1-naphthyl)-acetaldehyde (1.0 g, 4.99 mmol). The solution washeated to reflux under nitrogen atmosphere for 40 hours. The reactionmixture was cooled to ambient temperature and the crude product isolatedby filtration. Recrystallization from ethyl alcohol/2-butanone affordedproduct as a pale solid (705 mg). (mp. 245.3° C.).

    ______________________________________                                        Analysis:      Calculated                                                                              Found                                                ______________________________________                                        C              73.36     73.29                                                H              6.41      6.64                                                 N              7.13      7.12                                                 ______________________________________                                    

EXAMPLE 3 Preparation of (±)6-methyl-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole##STR23##

To methanesulfonic acid (215 mL) was added phosphorus pentoxide (31.8 g)slowly with stirring. After the addition was complete, the mixture wasfurther stirred under nitrogen atmosphere for 2 hours until homogeneous.To this solution was added 1-naphthylacetonitrile (50 g, 0.3 mol) in asingle portion, followed by 2-methyl-2,4-pentanediol (76.4 mL, 0.6 mol)dropwise at such a rate as to maintain a temperature between 25° and 30°C. (1 hour). After complete addition, the reaction mixture was stirredat ambient temperature for 10 hours and poured onto ice (500 g). Themixture was made basic with sodium hydroxide solution (50%), added atsuch a rate as to keep the temperature below 35° C. The mixture wasextracted with diethyl ether (3×250 mL) and the combined organic phaseswere dried over magnesium sulfate and concentrated under reducedpressure to afford a green solid.

Recrystallization from ethyl acetate afforded intermediate product (28.3g) which was used without further purification. ##STR24##

To a cooled (-78° C.) solution of previously prepared intermediateproduct (28.3 g, 0.106 mol) in THF (475 mL) under argon atmosphere wasadded t-butyllithium solution (68.4 mL, 1.7M in pentane, 0.116 mol)dropwise via syringe with stirring over 15 minutes. After completeaddition, the orange solution was stirred at -78° C. for 30 minutes.Methyl iodide (6.6 mL, 0.106 mol) was added dropwise via syringe and theresulting solution further stirred at -78° C. for 45 minutes.t-Butyllithium (68.4 mL, 1.7M in pentane, 0.116 mol) was added dropwiseover 15 minutes and the orange solution stirred for 2 hours. The mixturewas poured into ice/water (500 mL) and was acidified to pH 2-3 with 5NHCl solution. The mixture was extracted with diethyl ether (2×100 mL)and these extracts were discarded. The aqueous phase was made basic withsodium hydroxide solution (50%), cooling the mixture with ice whennecessary. The basic aqueous phase was extracted with diethyl ether(2×200 mL) and the combined organic extracts were dried over magnesiumsulfate, filtered and concentrated to afford product as an oily solid(13.15 g), which was used without further purification. ##STR25##

To a stirred cooled (-40° C.) solution of previous product (13.15 g,46.7 mmol) in THF (100 mL) and ethyl alcohol (100 mL) was added 5N HClsolution until pH 7. In a separate flask, a solution of sodiumborohydride (2.52 g, 65.8 mmol) was dissolved in water (20 mL) to which1 drop of 50% sodium hydroxide had been added. Portions of the sodiumborohydride solution and 5N HCl solution were alternately added to thereaction mixture such that the pH remained 6-8, at such a rate as tomaintain temperature between -35° and -45° C. After complete addition,the reaction mixture was warmed to ambient temperature over about 2hours. The reaction mixture was made basic with sodium hydroxidesolution and extracted with diethyl ether (3×100 mL). The combinedorganic phases were washed with brine and dried over magnesium sulfate.Filtration and removal of solvent afforded crude product (13.2 g) as aviscous oil, which was used without further purification. ##STR26##

A mixture of crude product from the previous reaction (13.2 g, 46.6mmol) and oxalic acid dihydrate (19.1 g, 152 mmol) in water (380 mL) washeated to reflux for 12 hours. The mixture was cooled to ambienttemperature and extracted with chloroform (2×100 mL). The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated to afford aldehyde as an orange oil. Distillation(Kugelrohr) under reduced pressure afforded pure aldehyde (1.97 g) as apale oil. ##STR27##

A solution of 5-methyltryptamine hydrochloride (1.11 g, 5.27 mmol) and2-(1-naphthyl)propionaldehyde (0.97 g, 5.26 mmol) in 95% ethyl alcoholwas heated to reflux for 48 hours under nitrogen atmosphere. The mixturewas cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between aqueous potassiumcarbonate solution and chloroform. The chloroform phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to flash chromatography on silica gel (25% methyl alcoholin chloroform as eluent), affording 529 mg of the higher rf isomer and200 mg of the lower rf isomer. Each diastereomer, independently, wasdissolved in ethyl acetate and treated with excess maleic acid. Themaleate salts were isolated by filtration affording 570 mg of isomer A(+) and 30 mg of isomer B (-).

isomer A data: m/e=340

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.66     73.64                                                H              6.18      6.13                                                 N              6.14      6.44                                                 ______________________________________                                    

isomer B data: m/e=340

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.66     73.41                                                H              6.18      6.04                                                 N              6.14      5.89                                                 ______________________________________                                    

EXAMPLE 4 Preparation of (±)6-(1,1-dimethylethyl)-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR28##

4-Chlorobutyryl chloride (300 g, 2.13 mol) was dissolved in dry THF (3L). To this solution was added 2,6-lutidine (252 mL) followed by 5% Pd/C(30 g). This mixture was placed in a Parr hydrogenator and shaken under60 psi of hydrogen for 6 hours. The mixture was purged with nitrogen,filtered, washing the catalyst with THF (500 mL), and concentrated atroom temperature under reduced pressure. Distillation afforded4-chlorobutanal (148.3 g) as a colorless liquid. ##STR29##

To a stirred suspension of 4-isopropylphenylhydrazine hydrochloridemonohydrate (15.3 g, 91.95 mmol) in chloroform (250 mL) was addedsaturated sodium carbonate solution (250 mL). The mixture was stirredfor 30 minutes until the organic phase appeared homogeneous, andextracted with chloroform (2×200 mL). The combined organic phases wereconcentrated to afford the hydrazine free base as a yellow oil. This oilwas dissolved in methanol (200 mL) and water (5 mL) and treated withsodium acetate (6.72 g, 82 mmol) and 4-chlorobutanal (8.7 g, 82 mmol).The mixture was placed in a sealable tube and purged with nitrogen for10 minutes. The tube was sealed and placed in an oil bath preheated to100° C. Heating was continued for 18 hours. The resulting dark solutionwas cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between chloroform/methanol (75/25by volume) and aqueous sodium carbonate solution. The organic phase wasconcentrated and the crude indole ethanamine was purified by flashchromatography on silica gel (0-25% methanol gradient in chloroform aseluent). Fractions containing product were combined and concentrated.The oil was dissolved in diethyl ether (300 mL) containing 1% methanoland treated with dry HCl gas. The hydrochloride salt was isolated byfiltration, washed with 2-propanol (50 mL) and diethyl ether (100 mL)and dried to afford 5-isopropyltryptamine hydrochloride (9.8 g) as apale solid, which was used without further purification. ##STR30##

A solution of 5-isopropyltryptamine hydrochloride (1.24 g, 5.19 mmol)and 2-(1-naphthyl)propionaldehyde (0.95 g, 5.16 mmol) in 95% ethylalcohol was heated to reflux for 48 hours under nitrogen atmosphere. Themixture was cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between aqueous potassiumcarbonate solution and chloroform. The chloroform phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to flash chromatography on silica gel (25% methyl alcoholin chloroform as eluent), affording 500 mg of the higher rf isomer alongwith 400 mg of impure lower rf isomer. The major diastereomer wasdissolved in ethyl acetate and treated with excess maleic acid. Thehydrochloride salt was isolated by filtration affording 400 mg of namedproduct as a pale solid.

m/e=369.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.36     74.58                                                H              6.66      6.64                                                 N              5.78      5.81                                                 ______________________________________                                    

EXAMPLE 5 Preparation of (±)6-methyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR31##

A solution of 1-naphthaldehyde (25.0 g, 0.16 mol), N-acetylglycine (19.0g, 0.162 mol) and sodium acetate (13.1 g, 0.160 mol) in acetic anhydride(147 mL) was heated to 100° C. for 4 hours. The reaction mixture wascooled to ambient temperature poured onto ice (300 mL) with stirring.The product was isolated by filtration, washed with water (3×50 mL) anddiethyl ether (3×50 mL) and dried under reduced pressure (11.82 g).##STR32##

A suspension of azalactone prepared above (3.15 g, 13.3 mmol) and5-methyltryptamine hydrochloride (2.0 g, 9.5 mmol) in 1N HCl (50 mL) washeated to reflux for 24 hours under nitrogen atmosphere. The reactionmixture was cooled to ambient temperature and the crude product isolatedby filtration. The brown solid was triturated with isopropyl alcohol(3×50 mL) and washed with diethyl ether (3×50 mL). Recrystallizationfrom ethanol afforded 1.94 g of desired product as the hydrochloridesalt.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.12     76.03                                                H              6.39      6.22                                                 N              7.72      7.52                                                 ______________________________________                                    

EXAMPLE 6 Preparation of (±)8-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR33##

To a stirred suspension of 2-bromophenylhydrazine hydrochloride (25.8 g,115 mmol) in chloroform (500 mL) was added saturated sodium carbonatesolution (500 mL). The mixture was stirred for 30 minutes until theorganic phase appeared homogenous, and extracted with chloroform (2×200mL). The combined organic phases were concentrated to afford thehydrazine free base as a yellow oil. This oil was dissolved in methanol(100 mL) and treated slowly with 4-chlorobutanal (prepared as describedin Example 4) (12.3 g, 115 mmol). The mixture was placed in a sealabletube and purged with nitrogen for 10 minutes. The tube was sealed andplaced in an oil bath preheated to 95° C. Heating was continued for 18hours. The resulting dark solution was cooled to ambient temperature andconcentrated under reduced pressure. The residue was partitioned betweenchloroform/methanol (75/25 by volume) and aqueous sodium carbonatesolution. The organic phase was concentrated and the crude indoleethanamine was purified by flash chromatography on silica gel (0-25%methanol gradient in chloroform as eluent). Fractions containing productwere combined and concentrated. The oil was dissolved in diethyl ether(300 mL) containing 1% methanol and treated with dry HCl gas. Thehydrochloride salt was isolated by filtration, washed with 2-propanol(50 mL) and diethyl ether (100 mL) and dried to afford 7-bromotryptaminehydrochloride (3.6 g) as a pale solid, which was used without furtherpurification. ##STR34##

A suspension of azalactone (prepared as described in Example 5) (55 g,6.53 mmol) and 7-bromotryptamine hydrochloride (1.50 g, 5.44 mmol) in 1NHCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthe crude product isolated by filtration. The brown solid was trituratedwith isopropyl alcohol (3×50 mL) and washed with diethyl ether (3×50mL). Recrystallization from ethanol afforded 260 mg of desired productas the hydrochloride salt. (mp=231°-233° C., dec.)

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              61.77     61.48                                                H              4.71      4.63                                                 N              6.55      6.73                                                 ______________________________________                                    

EXAMPLE 7 Preparation of (±)6-methyl-8-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole##STR35##

To a stirred, cooled (-5° C. solution of 2-bromo-4-methyl-aniline (50.54g, 0.272 mol) in concentrated HCl solution (200 mL) was added sodiumnitrite (18.9 g, 0.274 mol) in water (200 mL) dropwise at such a rate asto maintain temperature below 5° C. After complete addition, the mixturewas further stirred at 5° C. for 30 minutes. A solution of tin chloridemonohydrate (185.4 g, 0.822 mol) in concentrated HCl (total volume 400mL) was added dropwise again maintaining temperature below 5° C. Aftercomplete addition and 30 minutes of further stirring, the mixture wasplaced in the freezer overnight. The light brown solid whichprecipitated was isolated by filtration and washed with cold brinefollowed by a solution of petroleum ether/diethyl ether (2/1 by volume).This solid was slowly added to an ice cooled mixture of 50% sodiumhydroxide solution/ethyl acetate. The mixture was extracted with ethylacetate and the organic phase dried over magnesium sulfate. Afterfiltration, the solution was concentrated to 400 mL total volume,diluted with diethyl ether (1.5 L) and treated with dry HCl. Theproduct, 2-bromo-4-methyl-phenylhydrazine hydrochloride (52.4 g) wasisolated as a light brown solid and used without further purification.##STR36##

5-Methyl-7-bromotryptamine hydrochloride (4.95 g) was prepared asdescribed in Example 6, except using 2-bromo-4-methylphenylhydrazinehydrochloride (21 g) as starting material. ##STR37##

A suspension of azalactone (prepared as described in Example 5) (1.44 g,6.07 mmol) and 5-methyl-7-bromotryptamine hydrochloride (1.12 g, 3.87mmol) in 1N HCl (80 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (840 mg) byfiltration. (mp=203°-205° C., dec.)

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              62.20     62.44                                                H              4.83      5.07                                                 N              5.37      5.56                                                 ______________________________________                                    

EXAMPLE 8 Preparation of (±)8-methoxy-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole##STR38##

To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazinehydrochloride (14.44 g, 83 mmol) in THF (600 mL) was added4-chlorobutanal prepared as described in Example 5 (9.0 g, 84 mmol)followed by dropwise addition of triethylamine (8.6 g, 85 mmol) in THF(20 mL). Upon complete addition, the cooling bath was removed and thesolution stirred for 1 hour. The reaction mixture was filtered and thefilter cake washed with THF (100 mL). The combined filtrates wereconcentrated to an orange oil, which was dissolved in methanol (150 mL)and water (5 mL). The solution was transferred to a sealable tube andpurged with nitrogen for 10 minutes. The tube was sealed and placed inan oilbath preheated to 95° C. After heating for 14 hours, the reactionmixture was cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between saturated aqueouspotassium carbonate and 3:1 chloroform:2-propanol. The organic phase wasdried over sodium sulfate and concentrated. The residue was purified byflash chromatography on silica gel (15% methanol, 0.2% NH₄ OH, inchloroform as eluent). The fractions containing product were pooled andconcentrated under reduced pressure. The residue was dissolved inmethanol and treated with dry HCl and concentrated to afford7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which wasused without further purification. ##STR39##

A suspension of azalactone (prepared as described in Example 5) (1.30 g,5.5 mmol) and 7-methoxytryptamine hydrochloride (1.08 g, 4.8 mmol) in 1NHCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (880 mg ) byfiltration. (mp=226°-227° C., dec.)

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.73     70.61                                                H              5.72      5.77                                                 N              6.11      6.03                                                 ______________________________________                                    

EXAMPLE 9 Preparation of (±)6-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole##STR40##

A suspension of azalactone (prepared as described in Example 5) (1.4 g,5.9 mmol) and 5-bromotryptamine hydrochloride (1.77 g, 6.4 mmol) in 1NHCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (540 mg) byfiltration. (mp=234°-235° C., dec.) m/e=390.

    ______________________________________                                        Analysis       Calculated    Found                                            ______________________________________                                        C              61.55         61.38                                            H              4.57          4.64                                             N              5.52          5.29                                             ______________________________________                                    

EXAMPLE 10 Preparation of (±)7-methyl-8-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR41##

6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 7,except using 2-bromo-3-methylphenylhydrazine hydrochloride as startingmaterial. ##STR42##

A suspension of azalactone (prepared as described in Example 5) (1.07 g,4.51 mmol) and 6-methyl-7-bromotryptamine hydrochloride (1.22 g, 4.21mmol) in 1N HCl (70 mL) was heated to reflux for 65 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated with dryHCl. The product was isolated as the hydrochloride salt (840 mg) byfiltration. (mp=276°-279° C., dec.)

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              62.53     62.79                                                H              5.02      4.96                                                 N              6.34      6.19                                                 ______________________________________                                    

EXAMPLE 11 Preparation of (±)6-cyclohexyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR43##

4-Cyclohexylphenylhydrazine hydrochloride (35.6 g) was prepared asdescribed for 2-bromo-4-methylphenylhydrazine hydrochloride in Example7, except using 4-cyclohexylaniline as starting material. ##STR44##

5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as describedfor 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using4-cyclohexylphenylhydrazine hydrochloride as starting material.##STR45##

A suspension of azalactone (prepared as described in Example 5) (1.09 g,4.59 mmol) and 5-cyclohexyltryptamine hydrochloride (1.28 g, 4.59 mmol)in 1N HCl (70 mL) was heated to reflux for 14 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthe crude product isolated by filtration. The solid was recrystallizedfrom ethanol (2×) to afford 690 mg of desired product as a pale solidhydrochloride salt.

m/e=395

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.03     78.26                                                H              7.25      7.06                                                 N              6.50      6.48                                                 ______________________________________                                    

EXAMPLE 12 Preparation of (±)2,6-dimethyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride ##STR46##

To an aqueous solution (200 mL) of5-methyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolehydrochloride (2.00 g, 5.51 mmol) previously prepared in Example 5, wasadded formic acid (4.1 mL) and formaldehyde solution (0.8 mL of 37%aqueous solution). The mixture was heated to reflux for 72 hours. Thesolution was made basic with saturated potassium carbonate solution andextracted with chloroform (2×100 mL). The combined organic phases weredried over potassium carbonate and concentrated under reduced pressure.The crude product was purified by flash chromatography on silica gel(chloroform as eluent). The fractions containing product were pooled andconcentrated to a viscous oil. The oil was dissolved in diethyl etherand treated with anhydrous HCl and the resulting hydrochloride salt wasisolated by filtration. Drying afforded the named product (1.34 g).m/e=340.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.48     76.58                                                H              6.68      6.63                                                 N              7.43      7.28                                                 ______________________________________                                    

EXAMPLE 13 Preparation of (±)5-fluoro-6-methyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole##STR47##

3-fluoro-4-methyl-phenylhydrazine hydrochloride (21.4 g -) was preparedas described for 2-bromo-4-methylphenylhydrazine hydrochloride inExample 7, except using 3-fluoro-4-methylaniline as starting material.##STR48##

4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 7,except using 3-fluoro-4-methylphenylhydrazine hydrochloride (6.00 g) asstarting material. ##STR49##

A suspension of azalactone (prepared as described in Example 5) (2.3 g,9.6 mmol) and 4-fluoro-5-methyltryptamine hydrochloride (2.2 g, 9.6mmol) in 1N HCl (40 mL was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (520 mg) byfiltration.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.42     70.45                                                H              5.47      5.41                                                 N              6.08      6.10                                                 ______________________________________                                    

EXAMPLE 14 Preparation of (±)7,8,9,10-tetrahydro-10-(1-naphthalenylmethyl)-11H-benzo[g]pyrido[3,4-b]indole##STR50##

6,7-benzotryptamine hydrochloride was prepared (2.85 g) as described for5-methyl-7-bromotryptamine hydrochloride in Example 7, except using1-naphthylhydrazine hydrochloride (6.00 g) as starting material.##STR51##

A suspension of azalactone (prepared as described in Example 5) (2.75 g,11.6 mmol) and 6,7-benzotryptamine hydrochloride (2.85 g, 11.6 mmol) in1N HCl (50 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (300 mg) byfiltration. m/e=363.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.30     75.04                                                H              5.48      5.36                                                 N              5.85      5.76                                                 ______________________________________                                    

EXAMPLE 15 Preparation of (±)6-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4b]indole##STR52##

5-(1,1-dimethylethyl)-tryptamine hydrochloride was prepared (2.95 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 7,except using 4-(1,1-dimethylethyl)phenylhydrazine hydrochloride (6.00 g)as starting material. ##STR53##

A suspension of azalactone (prepared as described in Example 5) (1.25 g,5.26 mmol) and 5-(1,1-dimethylethyl)-tryptamine hydrochloride (1.33 g,5.26 mmol) in 1N HCl (50 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The solvent was removed underreduced pressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (700 mg) byfiltration.

m/e=369

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.36     74.08                                                H              6.66      6.69                                                 N              5.78      5.69                                                 ______________________________________                                    

EXAMPLE 16 Preparation of (±)6-(1-methylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4b]indole##STR54##

A suspension of azalactone (prepared as described in Example 5) (1.75 g,7.38 mmol) and 5-isopropyltryptamine hydrochloride (prepared asdescribed in Example 4) (1.76 g, 7.37 mmol) in 1N HCl (40 mL) was heatedto reflux for 24 hours under nitrogen atmosphere. The reaction mixturewas cooled to ambient temperature, neutralized with saturated aqueouspotassium carbonate solution and extracted with chloroform. The solventwas removed under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with maleic acid. The product was isolated as the maleate salt(671 mg ) by filtration. m/e=355

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.02     74.08                                                H              6.43      6.21                                                 N              5.95      5.83                                                 ______________________________________                                    

EXAMPLE 17 Preparation of (±)6,9-dimethyl-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4-b]indolehydrochloride ##STR55##

To a stirred suspension of 5-methyltryptamine hydrochloride (10.0 g,43.2 mmol) in chloroform (300 mL) was added saturated sodium carbonatesolution (300 mL). The mixture was stirred at ambient temperature for 1hour. The layers were separated and the aqueous layer was back extractedwith chloroform (2×100 mL). The combined organic layers were dried oversodium sulfate and concentrated. The residue was dissolved in toluene(300 mL) and treated with phthalic anhydride (7.05 g, 47.6 mmol). Thesolution was heated to reflux for 14 hours with azeotropic removal ofwater (by Dean-Stark trap). The solution was cooled to ambienttemperature and concentrated to afford crude product as a pale foam.Recrystallization from ethanol afforded product phthalimide (13.52 g) asa white solid, which was used without further purification. ##STR56##

To a stirred, cooled (0° C.) suspension of potassium hydride (25% oildispersion, 8.24 g, 51.3 mmol) in dry THF (50 mL) was added a solutionof phthalimide prepared above (13.02 g, 42.8 mmol) in THF (150 mL) over30 minutes. After complete addition, the mixture was further stirred for1 hour. Tetramethylethylenediamine (7.7 mL, 51.3 mmol) was added,followed by methyl iodide (4.0 mL, 63.8 mmol). After 1 hour, thereaction was quenched by addition of water (200 mL), followed byextraction with diethyl ether (2×100 mL). The combined organic phaseswere dried over magnesium sulfate and concentrated under reducedpressure to afford product as a yellow solid (14 g) which was usedwithout further purification. ##STR57##

A solution of phalimide prepared in the previous step (14 g, 42.8 mmol)in methanol (85 mL) was treated with hydrazine (3.4 mL, 109 mmol). Themixture was heated to reflux for 2 hours. The mixture was cooled toambient temperature, treated with concentrated HCl (7 mL) and methanol(25 mL), and further heated to reflux for 14 hours. After cooling toambient temperature, the mixture was partitioned between chloroform (200mL) and saturated aqueous sodium carbonate solution (200 mL). Theaqueous layer was further extracted with chloroform (2×100 mL) and theorganic phases combined, dried over sodium sulfate and concentrated. Thecrude product was purified by flash chromatography on silica gel (0-25%methanol in chloroform/0.2% NH₄ OH as eluent). The product containingfractions were pooled and concentrated under reduced pressure. Theresidue was dissolved in diethyl ether and treated with anhydrous HCl.The product 1,5-dimethyltryptamine hydrochloride (6.08 g) was isolatedby filtration as a tan solid and used without further purification.##STR58##

A suspension of azalactone prepared as described in Example 5 (1.06 g,4.45 mmol) and 1,5-dimethyltryptamine hydrochloride (1.00 g, 4.47 mmol)in 1N HCl (50 mL) was heated to reflux for 48 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthe crude product isolated by filtration. The brown solid was trituratedwith isopropyl alcohol (3×50 mL) and washed with diethyl ether (3×50mL). Recrystallization from ethanol afforded 710 mg of desired productas the hydrochloride salt.

m/e=340.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.48     76.78                                                H              6.68      6.58                                                 N              7.43      7.50                                                 ______________________________________                                    

EXAMPLE 18 Preparation of(-)-(S)-6-methyl-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4-b]indolehydrochloride ##STR59##

To a stirred solution of6-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (3.14 g, 16.9 mmol)in dry xylenes (65 mL) was added(S)-N,N-dimethyl-N'-(1-tert-butoxy-3-methyl)-2-butylformamidine (3.79 g,17.7 mmol) followed by camphorsulfonic acid (200 mg). The resultingsolution was heated to reflux for 72 hours. The solution was cooled toambient temperature and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (1:3:6triethylamine:ethyl acetate:hexanes as eluent). The product containingfractions were pooled and concentrated to afford the product formamidine(5.99 g) as a viscous oil which was used without further purification.##STR60##

To a stirred, cooled (0° C.) suspension of potassium hydride (25% oildispersion, 829 mg, 20.2 mmol) in THF (10 mL) was added formamidineprepared above (5.99 g, 16.8 mmol) in THF (45 mL). To this mixture wasadded tetramethylethylenediamine (3.0 mL, 20.2 mmol) followed bychloromethylmethyl ether (1.9 mL, 25.2 mmol). The mixture was stirredfor an additional 1 hour and treated with water (50 mL). The mixture waspartitioned between diethyl ether and water and the layers separated.The aqueous phase was extracted with diethyl ether (2×100 mL) and theorganic phases combined, dried over potassium carbonate, andconcentrated to afford product (6.73 g) as an orange oil, which was usedwithout further purification. ##STR61##

To a stirred, cooled (-78° C.) solution of previously preparedformamidine (3.36 g, 8.4 mmol) in dry THF (55 mL) was added n-BuLi (1.7Msolution in hexanes, 5.4 mL, 9.18 mmol) dropwise over 5 minutes. Thesolution was further stirred at -78° C. solution for 1 hour and treatedwith 1-chloromethylnaphthalene (1.62 g, 9.18 mmol) in dry THF (10 mL).The solution was further stirred for 4 hours at -78° C. and allowed towarm to room temperature overnight. Wet THF was added (50 mL) and thesolution was concentrated under reduced pressure. The residue wasdissolved in chloroform and washed with water. The organic phase wasdried over sodium carbonate and concentrated. The crude product waspurified by flash chromatography on silica gel (1:3:6triethylamine:ethyl acetate:hexanes as eluent). The product containingfractions were pooled and concentrated to afford product (3.48 g) as aviscous oil (m/e=539) which was used without further purification.##STR62##

To a stirred solution of methoxymethyl indole prepared above (3.48 g,6.45 mmol) in THF (30 mL) was added 2N HCl (30 mL). The mixture wasstirred at ambient temperature for 24 hours, and partitioned betweendiethyl ether and water. The aqueous phase was back extracted withdiethyl ether (2×50 mL) and the combined organic phases were washed withbrine, dried over sodium carbonate, and concentrated under reducedpressure. The residue was dissolved in THF (20 mL) and treated with 2Nsodium hydroxide solution (6 mL). After 2 hours, the reaction mixturewas extracted with chloroform (2×100 mL). The organic phase was driedover sodium carbonate and concentrated to afford product (2.68 g) as aviscous oil. (m/e=495). ##STR63##

To a stirred, cooled (0° C.) solution of previously prepared formamidine(2.68 g, 5.41 mmol) in ethanol (100 mL) was added water (12 mL) followedby acetic acid (12 mL) and hydrazine hydrate (22 mL). The reactionvessel was placed in the freezer (-10° C.) for 72 hours. The mixture waswarmed to ambient temperature and concentrated under reduced pressure.The crude product was dissolved in chloroform (300 mL) and washed withwater (3×50 mL). The organic phase was dried over sodium carbonate andconcentrated to a viscous oil. The oil was dissolved in diethyl etherand treated with anhydrous HCl. The hydrochloride salt (1.50 g) wasisolated by filtration. Recrystallization from ethanol (2×) affordedmaterial of constant rotation. Chiral HPLC confirmed

enantiomeric purity as >95% ee. (m/e=326)

specific rotation @589 nM=-40.21 (pyridine, C=1)

specific rotation @365 nM=+80.43 (pyridine, C=1)

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.12     75.96                                                H              6.39      6.56                                                 N              7.72      7.44                                                 ______________________________________                                    

EXAMPLE 19 Preparation of6-methyl-1-[(4-dimethylaminonaphthalenyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoledihydrochloride-monohydrate ##STR64##

To a stirred, cooled (-78° C.) suspension ofmethoxymethyltriphenylphosphonium chloride (10.32 g, 30.1 mmol) in dryTHF (150 mL) was added n-BuLi solution (18.8 mL. 1.6M, 30.1 mmol)dropwise by syringe. The orange suspension was stirred at -78° C. for 15min. A solution of 4-dimethylamino-1-naphthaldehyde (5.00 g, 25.1 mmol)in THF (75 mL) was added to the ylide dropwise over 10 min. The reactionmixture was gradually warmed to ambient temperature and stirred 14H.Saturated ammonium chloride solution (100 mL) was added and the mixtureextracted with diethyl ether (3×50 mL). The combined organic phases weredried over sodium sulfate and concentrated under reduced pressure.Chromatography on silica gel, eluting with 15% ethyl acetate/hexanesafforded product (5.43 g) as a mixture of olefin isomers which was usedwithout further purification. ##STR65##

A mixture of 5-methyltryptamine hydrochloride (695 mg, 3.3 mmol) and1-methoxy-4'-dimethylamino-benzostyrene (1.00 g, 4.4 mmol) inacetonitrile (20 mL) and 1N HCl solution (150 mL) was heated to refluxfor 96H, with addition of 1 mL of conc HCl added at 4H. The reactionmixture was cooled to ambient temperature, neutralized with saturatedaqueous potassium carbonate solution and extracted with chloroform. Thecombined organic phases were concentrated under reduced pressure and theresidue chromatographed on silica gel (2.5% MeOH/chloroform/0.2% NH₄ OHas eluent). The fractions containing product were pooled andconcentrated under reduced pressure. The residue was dissolved in ethylacetate and treated with anhydrous HCl. The product was isolated as thedihydrochloride salt monohydrate(1.22 g) by filtration.

m.p. 231.3° C.

    ______________________________________                                        Analysis:      Calculated                                                                              Found                                                ______________________________________                                        C              65.21     65.30                                                H              6.79      6.60                                                 N              9.13      9.03                                                 ______________________________________                                    

As noted above, the compounds of the present invention are useful inblocking the effect of agonists at 5-HT_(1c) receptors. Thus, thepresent invention also provides a method for blocking 5-HT_(1c)receptors in mammals comprising administering to a mammal requiringblocking of a 5-HT_(1c) receptor a receptor blocking dose of a compoundof the invention.

The term "receptor blocking dose", as defined herein, means an amount ofcompound necessary to block a 5-HT_(1c) receptor followingadministration to a mammal requiring blocking of a 5-HT_(1c) receptor.The active compounds are effective over a wide dosage range. Forexample, dosages per day will normally fall within the range of about0.05 to about 250 mg/kg of body weight. In the treatment of adulthumans, the range of about 0.5 to 100 mg/kg, in single or divided doses,is preferred. However, it will be understood that the amount of thecompound actually administered will be determined by a physician inlight of the relevant circumstances, including the condition to betreated, the choice of compound to be administered, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the chosen route of administration, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. The compounds may be administered by a variety of routessuch as oral, transdermal, subcutaneous, intranasal, intramuscular, andintravenous routes.

A variety of physiologic functions have been shown to be subject to beinfluenced by 5-HT_(1c) receptors. Therefore, the compounds of thepresent invention can be used to treat a variety of disorders in mammalsassociated with these receptors. Such disorders include sleepingdisorders, eating disorders, including bulimia and obesity,thermoregulation, sexual disorders, hyperactivity, excessive aggression,alcoholism, anxiety, obsessive-compulsive disorders, depression, panicdisorders, Gilles de la Tourette syndrome, migraine headaches, andAlzheimer's Disease. Additionally, effects of the 5-HT_(1c) receptorindicate that the compounds of the present invention can be useful forrelieving the sensation of pain. Thus, the present invention alsoprovides methods for treating the above disorders and for relieving thesensation of pain.

Several examples of more specific disorders which may be treated usingcompounds of this invention include, but are not limited to: (numeralsin parenthesis refer to the DSM-III-R Classification Codes)Attention-deficit hyperactivity disorder (314.01), Conduct disorders(312.20, 312.00, 312.90), Primary degenerative dementia of the Alzheimertype, senile onset (290.30, 290.20, 290.21, 290.00), Primarydegenerative dementia of the Alzheimer type, presenile onset (290.11,290.12, 290.13, 290.10), Alcohol withdrawal delirium (291.00), Alcoholhallucinosis (291.30), Alcohol, dementia associated with alcoholism(291.20), cannabis, delusional disorder (292.11), cocaine, intoxication(305.60), hallucinogen, mood disorder (292.84), nicotine, withdrawal(292.00), phencyclidine or similarly acting arylcyclohexylamine,intoxication (305.90), other psychoactive substance, intoxication(305.90), delirium (293.00), dementia (294.10), Organic delusionaldisorder (293.81), organic hallucinosis (293.82), organic mood disorder(293.83), organic anxiety disorder (294.80), organic personalitydisorder (310.10), organic mental disorder (294.80), Schizophrenia,catatonic (295.21, 295.22, 295.23, 295.24, 295.25, 295.20),schizophrenia, disorganized (295.11, 295.12, 295.13, 295.14, 295.15,295.00), schizophrenia, paranoid (295.31, 295.32, 295.33, 295.34,295.35, 295.00), schizophrenia, undiffertiated (295.91, 295.92, 295.93,295.94, 295.95, 295.00), schizophrenia, residual (295.61, 295.62,295.63, 295.64, 295.65, 295.60), delusional (paranoid disorder (297.10),schizophreniform disorder (295.40), schizoaffective disorder (295.70),induced psychotic disorder (297.30), Bipolar disorder, mixed (296.61,296.62, 296.63, 296.64, 296.65, 296.66, 296.60), bipolar disorder, manic(296.41, 296.42, 296.43, 296.44, 296.45, 296.46, 296.40), bipolardisorder, depressed (296.51, 296.52, 296.53, 296.54, 296.55, 296.56,296.50), major depression, single episode (296.21, 296.22, 296.23,296.24, 296.25, 296.26, 296.20), major depression, recurrent (296.31,296.32, 296.33, 296.34, 296.35, 296.36, 296.30), obsessive compulsivedisorder (300.30), post-traumatic stress disorder (309.89), generalizedanxiety disorder (300.02), hypochondriasis (300.07), somatizationdisorder (300.81), male erectile disorder (302.72), intermittentexplosive disorder (312.34), impulse control disorder (312.39), paranoid(301.00), schizoid (301.20), schizotypal (301.22), antisocial (301.70),and borderline (301.83).

One particularly unexpected embodiment of this invention providesselective ligands for the 5-HT_(1c) receptor. Compounds with a highaffinity for the 5-HT_(1c) receptor generally are cross-reactive withthe 5-HT₂ receptor as well. Now 5-HT_(1c) receptors can be selectivelymodulated using compounds of this invention at rates set forth above forblocking the effects of agonists at 5-HT_(1c) receptors. The selectiveaffinity may provide treatments with fewer side effects and willfacilitate the development of additional therapeutic agents.

The compounds of the present invention have been found to displayexcellent activity in a 5-HT_(1c) receptor binding assay which measuresthe affinity of the compounds to bind to 5-HT_(1c) receptors.Conversely, compounds with selective 5-HT_(1c) activity displayed lowaffinity for the 5-HT₂ receptor. Therefore, the compounds were testedfor 5-HT₂ affinity to demonstrate the selective 5-HT_(1c) effect. Theassays were conducted by the following procedures.

5-HT_(1c) selective compounds can be identified using the followingbiological assay procedures. Compounds having a selective affinity forthe 5-HT_(1c) receptor have a low IC₅₀ in the 5-HT_(1c) receptor assayand a higher IC₅₀ in the 5-HT₂ receptor assay. As shown by Table II(below) the compounds prepared in Examples 3, 4, 5, 7, 10, 13, 15, and16 are particularly 5-HT_(1c) selective.

I. Biological Reagent Preparation.

Beef brain was removed immediately after slaughter, and choroid plexuswere dissected over ice. Male Sprague-Dawley rats weighing 125-150 g(Harlan Industries, Cumberland, Ind.) were killed by decapitation. Thebrain of each was immediately removed and the cerebral cortex wasdissected over ice. Tissues were homogenized in 9 volumes of 0.32 mol/Lsucrose and centrifuged at 1,000×g for 10 minutes. The supernatant wascentrifuged at 17,000×g for 20 minutes. The pellet was suspended in 100volumes of 50 mM Tris-HCL (pH7.4), incubated at 37° C. for 10 minutesand centrifuged at 50,000×g for 10 minutes, and the process was repeatedthree times. The final pellets were frozen at -70° C. and used within 2weeks. Pellets were rehydrated with physiological buffer prior to use.

II. Assay Procedure.

Radioligand binding assays for 5-HT_(1c) and 5-HT₂ receptors wereconducted according to described methods. The assays can be conducted asdescribed by Hoyer D., Functional correlates of serotonin 5-HT₁recognition sites, J. Receptor Res 8, 59-81 (1988) and Hoyer D., EngelG., Kalkman HO Molecular pharmacology of 5-HT₁ and 5-HT₂ recognitionsires in rat and pig brain membranes: Radio-ligand binding studies with[³ H]5-HT, [³ H]8-OH-DPAT, (-) [¹²⁵ I] iodocyanopindolol, [³H]mesulergine and [³ H]ketanserin, Eur. J. Pharmacol. 118, 13-23 (1985).

For 5-HT_(1c) receptor assays increasing concentrations of experimentalcompound, 50 mM Tris HCl buffer pH[7.4], and tritiated mesulergine (2.0nM) (³ H ligand) were combined in polystyrene tubes at room temperature.The reaction was initiated by the addition of the resuspended choroidplexus tissue which had been preincubated at 37° C. for 20 minutes. Thereaction mixture was incubated in a 37° C. water bath for 15 minutes.

For 5-HT₂ receptor assays increasing concentrations of experimentalcompound, 50 mM Tris HCl buffer pH [7.4], and tritiated ketanserin (1nM) (³ H ligand) were combined in polystyrene tubes at room temperature.The reaction was initiated by the addition of the resuspended ratcerebral cortex tissue which had been preincubated at 37° C. for 20minutes. The reaction mixture was incubated in a 37° C. water bath for30 minutes.

The above assays were modified after a number of compounds had beenscreened to accomodate the unexpectedly high potency of the compounds ofthis invention in the 5-HT_(1c) assay. The concentration range of theexperimental compound in the assays was changed from [0.1 to 1000 (nM)]to [0.1 to 100 (nM)] to optimize the use of reagents and analysis time.The IC₅₀ values in Table II which are over 100 nM were accumulatedbefore the modification of the concentration range of the experimentalcompound in the assay.

The reactions were terminated by rapid filtration, (Brandel CellHarvestor), through Whatman GF/B glass filters that had been presoakedin Tris buffer pH [7.4]. The filters were then washed 2 times with 5 mlof ice cold Tris buffer pH [7.4]. Washed filters were placed inscintillation vials and 10 ml RedySolv, (Brandel), was added and sampleswere counted in a Searle D-300 beta counter. Means and standard errorstatistics were calculated for triplicate experimental determinations incertain cases. Mean values were obtained from three or more separatedeterminations. The incubation time for the reaction mixture was 15minutes at 37° C.

Concentrations that caused a 50% inhibition of radioligand binding(IC₅₀) and Hill coefficient were obtained by computer-assistedregression analysis.

The results of the evaluation of certain compounds of the presentinvention in the 5-HT_(1c) and 5-HT₂ binding assays are set forth belowin Table II. In the Table, column 1 sets forth the Example Number of thecompound evaluated, columns 2 and 3 are the IC₅₀ (nM) values for the5-HT_(1c) and 5-HT₂ receptors respectively.

                  TABLE II                                                        ______________________________________                                        5-HT Receptor Binding Displacement Assay                                      Example         5-HT.sub.1c                                                                           5-HT.sub.2                                            ______________________________________                                         1              6.4     56.1                                                   2              **      **                                                     3              6       >100                                                   4              14      >100                                                   5              30      267                                                    6              13.2    40                                                     7              60      247                                                    8              63      65                                                     9              27      87                                                    10              44      142                                                   11              189     >100                                                  12              54      >100                                                  13              16      >100                                                  14              61      >100                                                  15              11      >100                                                  16              9       >100                                                  17              23      >100                                                  18              <100    108                                                   ______________________________________                                    

Certain compounds and tryptamine-like intermediates of the presentinvention are useful for modulating 5-HT_(2B) receptors. The compoundswhich are most useful for binding a 5HT_(2B) receptor can be identifiedusing the following procedures.

II. Radioligand Binding Studies for 5-HT_(2B) :

Membrane preparation from transformed cells. Suspension cells expressingthe cloned rat 5-HT_(2B) receptor were harvested by centrifugation at2,200×g for 15 min at 4° C. Kursar, J. D., D. L. Nelson, D. B.Wainscott, M. L. Cohen, and M. Baez, Mol. Pharmacol. 42: 549-557 (1992).Membranes for the binding assays were prepared by vortexing the pelletin 50 mM Tris-HCl, pH 7.4 (0.5×10⁹ cells/30 ml). The tissue suspensionwas then centrifuged at 39,800×g for 10 min at 4° C. This procedure wasrepeated for a total of three washes, with a 10 minute incubation at 37°C. between the first and second wash. The final pellet was homogenizedin 67 mM Tris-HCl, pH 7.4 (at 20-40 and 12.5 million cells/ml, originalcell number, for cells expressing low and relatively high levels of the5-HT_(2B) receptor, respectively) using a Tissumizer (Tekmar,Cincinnati, Ohio), setting 65 for 15 seconds.

[³ H]5-HT binding studies. Binding assays were automated using a Biomek1000 (Beckman Instruments, Fullerton, Calif.) and were performed intriplicate in 0.8 ml total volume. Membrane suspension, 200 μl,(0.04-0.27 mg protein) and 200 μl of drug dilution in water were addedto 400 μl of 67 mM Tris-HCl, pH 7.4, containing [³ H]5-HT, pargyline,CaCl₂, and L-ascorbic acid. Final concentrations of pargyline, CaCl₂ andL-ascorbic acid were 10 μM, 3 mM and 0.1%, respectively. Tubes wereincubated at 37° C. for 15 min or at 0° C. for 2 hours (bindingequilibria were verified for both of these conditions), then rapidlyfiltered using a Brandel cell harvester (Model MB-48R; Brandel,Gaithersburg, Md.) through Whatman GF/B filters which had been presoakedin 0.5% polyethylenimine and precooled with ice-cold 50 mM Tris-HCl, pH7.4. The filters were then washed rapidly four times with one mlice-cold 50 mM Tris-HCl, pH 7.4. The amount of [³ H]5-HT trapped on thefilters was determined by liquid scintillation spectrometry (ReadyProtein and Beckman LS 6000IC, Beckman Instruments, Fullerton, Calif.).For the saturation experiments, actual free radioligand concentrationswere determined by sampling the supernatant of parallel saturationexperiments in which bound radioactivity had been separated bycentrifugation. The concentration of [³ H]5-HT ranged from 0.02 to 5 nMand 0.6 to 63 nM for saturation experiments incubated at 0° C. and 37°C., respectively. 5-HT, 10 μM, or 1-naphthylpiperazine (1-NP), 10 μM,defined nonspecific binding. For competition experiments, six to twelveconcentrations of displacing drugs were used, spanning six log units,and the final concentration of [³ H]5-HT was 2 nM. Protein wasdetermined by the method of Bradford, using bovine serum albumin as thestandard. Bradford, M. M., Anal. Biochem. 72: 248-254 (1976).

Statistical Analysis:

The K_(d) and B_(max) values from the saturation assays were determinedfor best fit to a one-site or a two-site binding model using a partialF-test. De Lean, A., A. A. Hancock, and R. J. Lefkowitz, Mol. Pharmacol.21: 5-16 (1981). The following equation was used for a one-site bindingmodel, ##EQU1## where Bound=amount of [³ H]5-HT specifically bound,B_(max) =maximum number of binding sites, K_(d) =equilibriumdissociation constant and [L]=free concentration of [³ H]5-HT, or atwo-site binding model, ##EQU2## where Bound=amount of [³ H]5-HTspecifically Bound, B_(max1) =maximum number of high affinity bindingsites, B_(max2) =maximum number of low affinity binding sites, K_(d1)=equilibrium dissociation constant for the high affinity site, K_(d2)=equilibrium dissociation constant for the low affinity site and[L]=free concentration of [³ H]5-HT. The IC₅₀ values from thecompetition assays, the binding parameters for the IP₃ standard curveand the EC₅₀ and E_(max) values from the IP₃ assays were determined bynonlinear regression analysis of four parameter logistic equations(Systat, Systat Inc, Evanston, Ill.). De Lean, A., A. A. Hancock, and R.J. Lefkowitz, Mol. Pharmacol. 21: 5-16 (1981). The IC₅₀ values wereconverted to K_(i) values using the Cheng-Prusoff equation. Cheng, Y.,and W. H. Prusoff, Biochem. Pharmacol. 22: 3099-3108 (1973).

III. Assay Methods 5-HT2B in vitro:

Male Wistar rats (150-375 g; Laboratory Supply, Indianapolis, Ind.) weresacrificed by cervical dislocation, and longitudinal section of thestomach fundus were prepared for in vitro examination. Four preparationswere obtained from one rat fundus. Ring preparations of the extractedjugular vein were prepared as described by Hooker; Blood Vessels 14:1(1977) and Cohen, M. L. J. Pharamcol. Exp. Ther. 227:327 (1983). Tissueswere mounted in organ baths containing 10 mL of modified Krebs solutionof the following composition (millimolar concentrations): NaCl, 118.2,KCl, 4.6; CaCl₂.H₂ O, 1.6; KH₂ PO₄, 1.2; MgSO₄, 1.2; dextrose, 10.0; andNaHCO₃, 24.8. Tissue bath solutions were maintained at 37° C. andequilibrated with 95% O₂ and 5% CO₂. Tissues were placed under optimumresting force (4 g) and were allowed to equilibrate for approximately 1hour before exposure to the test compound. Isometric contractions wererecorded as changes in grams of force on a Beckman Dynograph withStatham UC-3 transducers.

Determination of Apparent Antagonist Dissociation Constant:

Noncumulative contractile concentration-response curves for serotonin inthe fundus and cumulative concentration response curves in the jugularvein were obtained by a stepwise increase in concentration after washingout the preceding concentrations every 15-20 minutes. Each agonistconcentration remained in contact with the tissue for approximately 2minutes and maximum response to each compound concentration wasmeasured. ED₅₀ values were taken as the concentration of agonist thatproduced half-maximal contraction. After control responses wereobtained, tissues were incubated with an appropriate concentration ofbuffer or antagonist for 1 hour. Responses to serotonin were thenrepeated in the presence of an antagonist. Concentration responsesutilized only one agonist and one antagonist concentration per tissue.In general, successive agonist responses in the presence of buffertreatment were unaltered (average dose ratio was 1.28±0.21).

Apparent antagonist dissociation constants (KB) were determined for eachconcentration of antagonist according to the following equation:

    K.sub.B =[B]/(dose ratio-1)

where [B] is the concentration of the antagonist and dose ratio is theED₅₀ of the agonist in the presence of the antagonist divided by thecontrol ED₅₀. Generally, parallel shifts in the concentration-responsecurves occurred in the presence of antagonists. The results wereexpressed as the negative logarithm of the K_(B) (i.e., -log K_(B)).Calculations were completed using known methods. Zaborowsky, B. R. J.Pharmacol. Methods 4:4165 (1980).

Compounds exhibiting activity at the 5HT_(2B) receptor are useful fortreating disorders related to the modulation of the 5HT_(2B) receptor.Compounds having 5HT_(2B) antagonist activity reduce the spasticity ofthe colon. These compounds are useful for the treatment of functionalbowel disorders including irritable bowel syndrome and irritable bowelsyndrome-related symptoms. The antispasmodic effect of such compoundscan reduce abdominal pain associated with functional bowel disorders.

As used herein the term "functional bowel disorder" refers to afunctional gastrointestinal disorder manifested by (1) abdominal painand/or (2) symptoms of disturbed defecation (urgency, straining, feelingof incomplete evacuation, altered stool form [consistency] and alteredbowel frequency/timing) and/or (3) bloating (distention). The term"functional bowel disorder" includes but is not limited to irritablebowel syndrome, hypermotility, ichlasia, hypertonic lower esophogealsphinctor, tachygastria, constipation, hypermotility associated withirritable bowel syndrome.

Compounds demonstrating activity at the 5HT_(2A) receptor can beutilized in the treatment or prevention of conditions related tomodulation of the 5HT_(2A) receptor. Examples of such conditions includehypertension, sleep disorders, hallucinogenic activity, psychosis,anxiety, depression, thermoregulation, feeding disorders, andhypotension. Leonard, B. E., International Clinical Psychopharmacology,7, 13-21 (1992).

While it is possible to administer a compound of the invention directlywithout any formulation, the compounds are preferably employed in theform of a pharmaceutical formulation comprising a pharmaceuticallyacceptable excipient and at least one compound of the invention. Suchcompositions contain from about 0.1 percent by weight to about 90.0percent by weight of a present compound. As such, the present inventionalso provides pharmaceutical formulations comprising a compound of theinvention and a pharmaceutically acceptable excipient therefor.

In making the compositions of the present invention, the activeingredient is usually mixed with an excipient which can be a carrier, ora diluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Whenthe carrier serves as a diluent, it can be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. Thus, the composition can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, emulsions,solutions, syrups, suspensions, aerosols (as a solid or in a liquidmedium), and soft and hard gelatin capsules.

The compounds of the invention may be delivered transdermally, ifdesired. Transdermal permeation enhancers and delivery systems,including patches and the like, are well known to the skilled artisan.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate,water, and mineral oil. The formulations may also include wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

The compounds of this invention may be delivered transdermally usingknown transdermal delivery systems and excipients. Most preferrably, acompound of this invention is admixed with permeation enhancersincluding, but not limited to, propylene glycol, polyethylene glycolmonolaurate, and azacycloalkan-2-ones, and incorporated into a patch orsimilar delivery system. Additional excipients including gelling agents,emulsifiers, and buffers may be added to the transdermal formulation asdesired.

For oral administration, a compound of this invention ideally can beadmixed with carriers and diluents and molded into tablets or enclosedin gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.1 to about 500 mg or more, usually about5 to about 300 mg, of the active ingredient. The term "unit dosage form"refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with a suitable pharmaceuticalcarrier.

In order to more fully illustrate the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as active compounds any of thecompounds of the present invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                                 Concentration                                                        Amount Per                                                                             by Weight                                                            Capsule  (percent)                                            ______________________________________                                        (+/-) 6-methyl-1-(1-(3-ethyl-                                                                   250 mg     55.0                                             amino naphthalenyl)-1-ethyl)-                                                 1,2,3,4-tetrahydro-9H-pyrido[3,4-                                             b]indole (Z) 2-butenedioate                                                   starch dried      200 mg     43.0                                             magnesium stearate                                                                               10 mg      2.0                                                               460 mg     100.0                                            ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Capsules each containing 20 mg of medicament are made as follows:

    ______________________________________                                                                 Concentration                                                        Amount Per                                                                             by Weight                                                            Capsule  (percent)                                            ______________________________________                                        6-(1-methylethyl)-1,2,3,4-                                                                      20 mg      10.0                                             tetrahydro-1-(1-(4-dimethyl-                                                  aminonaphthalenyl)-methyl)-9H-                                                pyrido[3,4b]indole(Z)-2-                                                      butenedioate                                                                  starch            89 mg      44.5                                             microcrystalline  89 mg      44.5                                             cellulose                                                                     magnesium stearate                                                                               2 mg      1.0                                                                200 mg     100.0  mg                                        ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 3

Capsules each containing 100 mg of medicament are made as follows:

    ______________________________________                                                                 Concentration                                                        Amount Per                                                                             by Weight                                                            Capsule  (percent)                                            ______________________________________                                        5-fluoro-6-methyl-1-(1-(3-methyl-                                                               100     mg     30.00                                        aminonaphthalenyl)-methyl)-                                                   1,2,3,4-tetrahydro-9H-pyrido-                                                 [3,4-b]indole (Z)-2-butenedioate                                              polyoxyethylene   50      mg      0.02                                        sorbitan                                                                      monooleate                                                                    starch powder     250     mg     69.98                                                          350.05  mg     100.00                                       ______________________________________                                    

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 4

Tablets containing 10 mg of active ingredient are made as follows:

    ______________________________________                                                                Concentration                                                        Amount Per                                                                             by Weight                                                            Capsule  (percent)                                             ______________________________________                                        7,8,9,10-tetrahydro-10-(1-(2-                                                                  10     mg      10.0                                          dimethylaminonaphthyleneyl)-                                                  methyl)-11H-benzo[g]-pyrido-                                                  [3,4-b]indole (Z)-2-butenedioate                                              starch           45     mg      45.0                                          microcrystalline cellulose                                                                     35     mg      35.0                                          polyvinylpyrrolidone (as 10%                                                                   4      mg      4.0                                           solution in water)                                                            sodium carboxymethyl starch                                                                    4.5    mg      4.5                                           magnesium stearate                                                                             0.5    mg      0.5                                           talc             1      mg      1.0                                                            100    mg      100.0                                         ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 5

A tablet formulation may be prepared using the ingredients below:

    ______________________________________                                                                Concentration                                                       Amount Per                                                                              by Weight                                                           Capsule   (percent)                                             ______________________________________                                        7-methyl-8-bromo-1-(1-cyclo-                                                                  250 mg      38.0                                              hexyleneyl-methyl)-1,2,3,4-                                                   tetrahydro-9H-pyrido-[3,4-b]                                                  indole hydrochloride                                                          microcrystalline cellulose                                                                    400 mg      60.0                                              silicon dioxide fumed                                                                          10 mg       1.5                                              stearic acid     5 mg        0.5                                                              665 mg      100.0                                             ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 6

Suspensions each containing 5 mg of medicament per 5 ml dose are asfollows:

    ______________________________________                                                              per 5 ml of                                                                   suspension                                              ______________________________________                                        6-methyl-1-(1-(4-fluoro-                                                                              5      mg                                             naphthalenyl)-methyl)-1,2,3,4-                                                tetrahydro-9H-pyrido[3,4-b]indole                                             hydrochloride                                                                 sodium carboxymethyl cellulose                                                                        50     mg                                             syrup                   1.25   ml                                             benzoic acid solution   0.10   ml                                             flavor                  q.v.                                                  color                   q.v.                                                  water                   q.s. to 5 ml                                          ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An aerosol solution is prepared containing the following components:

    ______________________________________                                                         Concentration by                                                              Weight (percent)                                             ______________________________________                                        5-methoxy-6-methyl-1-(1-                                                                          0.25                                                      naphthalenylmethyl)-1,2,3,4-                                                  tetrahydro-9H-pyrido[3,4-                                                     b]indole (Z)-2-butenedioate                                                   ethanol            29.75                                                      Propellant 22      70.00                                                      (chlorodifluoromethane)                                                                          100.00                                                     ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

We claim:
 1. A compound of the formula (I) ##STR66## wherein: R₁ ishydrogen or C₁ -C₃ alkyl;R₂ is hydrogen or C₁ -C₆ alkyl; R₃ is hydrogenor C₁ -C₃ alkyl; R₄ is bicyclic or substituted bicyclic; A is formulaIV: ##STR67## wherein R₆ and R₇ are, independently, hydrogen, C₁ -C₆alkyl, C₂ -C₆ alkenyl, halo, halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl,COR₅, C₁ -C₁₀ alkanoyl, CO₂ R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂,--SR₅, or OR₅ ; m is 1 or 2; R₅ is independently hydrogen or C₁ -C₄alkyl; R_(5') is C₁ -C₄ alkyl; R₈ is independently selected from thegroup consisting of an R₆ group, substituted C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl,substituted C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, C₇-C₁₆ arylalkyl; or a pharmaceutically acceptable salt or solvatethereof.
 2. A compound of claim 1 wherein R₁ is hydrogen.
 3. A compoundof claim 2 wherein R₃ is hydrogen or methyl.
 4. A compound of claim 3wherein R₂ is hydrogen or methyl.
 5. A compound of claim 4 wherein A isa group of the formula IV wherein R₆ and R₇ are independently selectedfrom the group consisting of hydrogen, C₁ -C₅ alkyl, and halo; R₈ isindependently selected from the group consisting of hydrogen, C₁ -C₅alkyl, halo and C₅ -C₈ cycloalkyl.
 6. A compound of claim 5 wherein R₆is C₁ -C₅ alkyl or halo; R₇ and R₈ are independently hydrogen, halo, orC₁ -C₅ alkyl.
 7. A compound of claim 5 wherein R₄ is naphthyl orsubstituted naphthyl.
 8. A compound of claim 5 wherein R₄ is substitutednaphthyl wherein the naphthyl substituents are selected from the groupconsisting of dialkylamino and monoalkylamino.
 9. A compound of claim 8wherein R₄ is substituted naphthyl wherein the naphthyl substituents aredialkylamino.
 10. A compound of claim 9 wherein R₄ is substitutednaphthyl wherein the naphthyl substituents are dimethylamino.
 11. Acompound of claim 1 wherein R₁ is hydrogen; R₂ is hydrogen or methyl; R₃is hydrogen; R₄ is dialkylamino substituted naphthyl; A is a group ofthe formula (IV) wherein R₆ is hydrogen; R₇ is hydrogen or methyl; R₈ isC₁ -C₄ alkyl, Br, or F; or a pharmaceutically acceptable salt or solvatethereof.
 12. A substantially pure stereoisomer of a compound of claim 1.13. A compound of claim 1 which is the substantially pure (-)enantiomer.
 14. A compound of claim 1 selected from the group consistingof6-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4-b]indole,6-(1-methylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4-b]indole,6-methyl-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,6-(1,1-dimethylethyl)-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,6-methyloxy-1-(2-methylaminonaphthalenyl)-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,6-(1,1-dimethylethyl)-1-(1-(3-diethylaminonaphthalenyl)-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,and6-methyl-1-[(4-dimethylaminonaphthalenyl)-methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole.15. A compound of claim 1 selected from the group consisting of(-)-(S)-6-methyl-1-[(4-dimethylaminonaphthalenyl)-methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,(-)-(S)-6-methyl-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,(-)-(S)-6-(1,1-dimethylethyl)-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole,and(-)-(S)-6-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido[3,4-b]indole.16. A pharmaceutical formulation comprising a compound of claim 1 andone or more pharmaceutically acceptable excipients therefor.
 17. Amethod for treating a mammal suffering from or susceptible to acondition associated with 5HT_(1c) modulation, which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) ##STR68## wherein: R₁ is hydrogen or C₁ -C₃ alkyl;R₂ ishydrogen or C₁ -C₆ alkyl; R₃ is hydrogen or C₁ -C₃ alkyl; R₄ is bicyclicor substituted bicyclic; A is formula IV: ##STR69## wherein R₆ and R₇are, independently, hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, or OR₅ ; m is 1 or 2; R₅is independently hydrogen or C₁ -C₄ alkyl; R_(5') is C₁ -C₄ alkyl; R₈ isindependently selected from the group consisting of an R₆ group,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃)alkyl, C₇ -C₁₆ arylalkyl; or a pharmaceuticallyacceptable salt or solvate thereof.
 18. A method of claim 17 forselectively binding 5-HT_(1c) receptors in mammals comprisingadministering to a mammal requiring selective binding of a 5-HT_(1c)receptor, a receptor binding dose of a 5-HT_(1c) selective compound ofFormula (I).